PROJECT SUMMARY/ABSTRACT This proposal is a resubmission of a competing renewal application for our study, ?Clinical Pharmacology of Electronic Cigarettes?. The FDA has deemed electronic cigarettes (EC) to be tobacco products that are to be regulated as such under the 2009 Family Smoking Prevention and Tobacco Control Act. Among the characteristics that are relevant to FDA regulation are the addictiveness and potential harm of ECs, both of which are determined in substantially by effects of nicotine. Regulations of ECs could include regulation of the device power, nature of coils and wicks, and the composition of EC liquids. A critical unresolved regulatory issue is whether there should be limit on the nicotine content of e-liquids. Based on evidence of nicotine titration in EC users, we question the proposition that setting an upper limit for nicotine content of e-liquids will benefit the health of smokers who are switching to EC to aid quitting cigarette smoking. We hypothesize the opposite ? namely that EC users will titrate their intake of nicotine such that they will inhale similar amount of nicotine but fewer aerosol toxicants and suffer less harm to health when using higher vs lower nicotine content e-liquids. Thus, we propose to study systemic nicotine exposure; nicotine-related subjective, cardiovascular (CV) and hormonal effects; exposure to non-nicotine toxicants (volatile organic compounds, such as acrolein and benzene); and biomarkers of CV disease (CVD) risk in EC users switched from low to high nicotine content e-liquids. If our hypothesis of lower potential risk with use of high nicotine concentration ECs is confirmed, it would suggest that federal regulation not place an upper limit on nicotine content, and that regulators might in some cases promote the use of higher rather than lower nicotine liquids for reasons of safety.